Production of amide derivatives and intermediate compounds therefor

ABSTRACT

A method for producing an amide derivative of the formula  XV! ##STR1## wherein each symbol is as defined in the specification, and an enantiomer thereof, a novel intermediate useful for producing said compound and a production method thereof. The production method of the present invention is extremely easy and simple as compared to the conventional methods, and enables effective production of compound  XV! at high yields, which includes compound  XVI! having an HIV protease inhibitory action. In addition, the novel intermediates of the present invention are extremely useful as intermediates for producing not only the aforementioned compound  XVI! but also compounds useful as X-ray contrast media.

This is a continuation of International Application No. PCT/JP96/02757,filed Sep. 24, 1996.

TECHNICAL FIELD

The present invention relates to a novel method for producing a compoundof the formula XVI! ##STR2## wherein Me is methyl, Bu-t is t-butyl andPh is phenyl, which is useful as a treatment drug of HIV-relateddiseases as a result of its inhibitory action on proteases derived fromviruses, various novel intermediate compounds useful for producing saidcompound XVI!, and to the method for production thereof. Theseintermediate compounds can be used not only for the production of theabove-mentioned compound XVI! but also for the production of variousother compounds.

BACKGROUND ART

The above-mentioned compound XVI! useful as an HIV protease inhibitor isknown as described in W095/09843. This compound XVI! has beenconventionally produced from serine as a starting material by increasingcarbon and through numerous other steps inclusive of stereoselectivereduction of carbonyl group. Such conventional production method isextremely complicated and inefficient, since it requires expensivestarting materials and constant low temperature conditions forreactions. Accordingly, there remain many problems to be solved beforethe conventional synthetic method is actually put to industrialpractice.

In addition, 2,2-dimethyl-6-amino-1,3-dioxepan-5-ol which is describedin, for example, U.S. Pat. No. 4,439,613 is an intermediate forproducing a compound useful as an X ray contrast medium, and even thoughthe compound obtained is a racemate, resolution of the racemate itselfby a method such as recrystallization has been extremely difficult.Moreover, this U.S. patent does not suggest production of a specificenantiomer of the present invention.

Accordingly, an object of the present invention is to provide a methodfor stereoselectively and extremely efficiently producing theabove-mentioned compound XVI! useful as an HIV protease inhibitor uponsolution of the above-mentioned problems. Another object of the presentinvention is to provide a novel intermediate compound useful forproducing said compound, and a production method thereof.

DISCLOSURE OF THE INVENTION

The present inventors have made intensive studies in an attempt toachieve the above-mentioned objects, and found that a step comprisingacetalating or ketalating (z)-2-butene-1,4-diol, and epoxidation of theobtained compound to give a 3,5,8-trioxabicyclo 5.1.0!octane derivative,which is followed by an epoxy ring-opening reaction using a chiralamine, leads to a stereospecific (5R,6S)-6-substitutedamino-1,3-dioxepan-5-ol derivative or an enantiomer thereof, from whicha compound of the following formula XV!, that is, a compound inclusiveof the aforementioned compound XVI! useful as an HIV protease inhibitor,can be extremely efficiently produced stereoselectively through variousother steps, which resulted in the completion of the present invention.

That is, the present invention provides the following (1) to (14).

(1) A (5R, 6S)-6-substituted amino-1,3-dioxepan-5-ol derivative of theformula VII! ##STR3## wherein R¹ and R² are the same or different andeach is a hydrogen atom, an alkyl or an aryl, or R¹ and R² combinedlyform a cycloalkyl ring together with the adjacent carbon atom, and R⁴ isan amino-protecting group, an enantiomer thereof and a salt thereof.

(2) A 1,3-dioxolan-4-yl-ethanol derivative of the formula VIII! ##STR4##wherein R¹ and R² are the same or different and each is a hydrogen atom,an alkyl or an aryl, or R¹ and R² combinedly form a cycloalkyl ringtogether with the adjacent carbon atom, and R⁴ is an amino-protectinggroup, an enantiomer thereof and a salt thereof.

(3) A method for producing a 1,3-dioxolan-4-yl-ethanol derivative of theformula VIII! ##STR5## wherein R¹, R² and R⁴ are as defined above, andan enantiomer thereof, comprising isomerizing a (5R,6S)-6-substitutedamino-1,3-dioxepan-5-ol derivative of the formula VII! ##STR6## whereinR¹, R² and R⁴ are as defined above, or an enantiomer thereof into a5-membered ring in the presence of an acid.

(4) A method for producing a 1,3-dioxolan-4-yl-ethanol derivative of theformula VIII! ##STR7## wherein R¹, R² and R⁴ are as defined above, andan enantiomer thereof, comprising protecting an amino group of a(5R,6S)-6-amino-1,3-dioxepan-5-ol derivative of the formula VI! ##STR8##wherein R¹ and R² are as defined above, or an enantiomer thereof, togive a (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol derivative of theformula VII! ##STR9## wherein R¹, R² and R⁴ are as defined above, anenantiomer thereof or a salt thereof, and isomerizing the obtainedcompound into a 5-membered ring in the presence of an acid.

(5) A 1,3-dioxolan-4-yl-ethylthio derivative of the formula IX!##STR10## wherein R¹, R² and R⁴ are as defined above, and R⁵ is ahydrogen atom, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted aryl or an optionallysubstituted aralkyl, an enantiomer thereof and a salt thereof.

(6) A method for producing a 1,3-dioxolan-4-yl-ethylthio derivative ofthe formula IX! ##STR11## wherein R¹, R², R⁴ and R⁵ are as definedabove, comprising reacting a 1,3-dioxolan-4-yl-ethanol derivative of theformula VIII! ##STR12## wherein R¹, R² and R⁴ are as defined above, oran enantiomer thereof, with a halogenating agent or a sulfonylatingagent, and reacting the obtained compound with a mercaptan of theformula

    R.sup.5 SH

wherein R⁵ is as defined above, for thioetherification.

(7) A 3-substituted aminobutane-1,2-diol derivative of the formula X!##STR13## wherein R⁴ and R⁵ are as defined above, an enantiomer thereofand a salt thereof.

(8) A method for producing a 3-substituted aminobutane-1,2-diolderivative of the formula X! ##STR14## wherein R⁴ and R⁵ are as definedabove, and an enantiomer thereof, comprising hydrolyzing a1,3-dioxolan-4-yl-ethylthio derivative of the formula IX! ##STR15##wherein R¹, R², R⁴ and R⁵ are as defined above, or an enantiomer thereofin the presence of an acid.

(9) A 3-substituted aminobutane derivative of the formula XI! ##STR16##wherein R⁴ and R⁵ are as defined above, R⁶ is a hydroxy-protecting groupand Z is a substituent which functions as a leaving group with an oxygenatom, an enantiomer thereof and a salt thereof.

(10) A method for producing a 3-substituted aminobutane derivative ofthe formula XI! ##STR17## wherein R⁴, R⁵, R⁶ and Z are as defined above,and an enantiomer thereof, comprising protecting a primary hydroxy of a3-substituted aminobutane-1,2-diol derivative of the formula X!##STR18## wherein R⁴ and R⁵ are as defined above, or an enantiomerthereof, and, with or without isolating the obtained compound,converting a secondary hydroxy to a leaving group.

(11) A substituted 1-butene oxide derivative of the formula XII!##STR19## wherein R⁴ and R⁵ are as defined above, an enantiomer thereofand a salt thereof.

(12) A method for producing a substituted 1-butene oxide derivative ofthe formula XII! ##STR20## wherein R⁴ and R⁵ are as defined above, andan enantiomer thereof, comprising treating a 3-substituted aminobutanederivative of the formula XI! ##STR21## wherein R⁴, R⁵, R⁶ and Z are asdefined above, or an enantiomer thereof, in the presence of a base, andsimultaneously conducting epoxidation and deprotection of primaryhydroxy.

(13) A method for producing a substituted 1-butene oxide derivative ofthe formula XII! ##STR22## wherein R⁴ and R⁵ are as defined above, andan enantiomer thereof, comprising protecting a primary hydroxy of a3-substituted aminobutane-1,2 diol derivative of the formula X!##STR23## wherein R⁴ and R⁵ are as defined above, or an enantiomerthereof, converting, with or without isolating the obtained compound, asecondary hydroxy to a leaving group to give a 3-substituted aminobutanederivative of the formula XI! ##STR24## wherein R⁴, R⁵, R⁶ and Z are asdefined above, or an enantiomer thereof, and treating the obtainedcompound in the presence of a base to simultaneously conduct epoxidationand deprotection of the primary hydroxy.

(14) A method for producing an amide derivative of the formula XV!##STR25## wherein R⁵ is as defined above, R⁷ and R⁸ are the same ordifferent and each is a hydrogen atom, an optionally substituted alkyl,an optionally substituted aryl, an optionally substituted heteroaryl oran optionally substituted aralkyl, or R⁷ and R⁸ combinedly form a heteroring together with the adjacent nitrogen atom, said hetero ring beingoptionally substituted by halogen atom, alkyl, alkenyl, alkoxy, amino,alkoxycarbonyl, carboxamide or alkyl-substituted carbamoyl, and R⁹ is anoptionally substituted alkyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl oran optionally substituted heteroarylalkyl, and an enantiomer thereof,comprising reacting a substituted 1-butene oxide derivative of theformula XII! ##STR26## wherein R⁴ and R⁵ are as defined above, or anenantiomer thereof, with an amine of the formula XIII! ##STR27## whereinR⁷ and R⁸ are as defined above, removing the amino-protecting group togive a 1,3-diamino-2-hydroxybutane derivative of the formula XIV!##STR28## wherein R⁵, R⁷ and R⁸ are as defined above, or an enantiomerthereof, and reacting the obtained compound with an acylating agent,followed by deprotection of the protecting group on R⁹ where necessary.

As used herein, alkyl may be linear or branched and preferably has 1 to6 carbon atoms. Specific examples thereof include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl,neopentyl, t-pentyl, hexyl, isohexyl, neohexyl and the like, withpreference given to lower alkyl having 1 to 4 carbon atoms such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl.

The optionally substituted alkyl includes, for example, theabove-mentioned alkyl which may be substituted by one or moresubstituent(s) which do(es) not influence the reaction. Examples of thesubstituents include hydroxy; halogen atoms such as fluorine, chlorine,bromine and iodine; amino; nitro; mono- or dialkylamino having 1 to 6carbon atom(s) such as methylamino, ethylamino, hexylamino,dimethylamino and diethylamino; cyano; cycloalkyl having 3 to 7 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl; alkoxy having 1 to 6 carbon atom(s) such as methoxy,ethoxy, propoxy, butoxy, pentyloxy and hexyloxy; carboxyl;alkoxycarbonyl having 2 to 6 carbon atoms such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and pentyloxycarbonyl;and the like. Preferred are hydroxy, halogen atom and amino.

The position and number of substituents on alkyl are not particularlylimited.

The alkenyl may be linear or branched and preferably has 2 to 6 carbonatoms. Examples thereof include vinyl, allyl, crotyl, 2-pentenyl,3-pentenyl, 2-hexenyl, 3-hexenyl, and the like, with preference given tothose having 2 to 4 carbon atoms, such as vinyl, allyl and crotyl.

The optionally substituted alkenyl is that which may be substituted byone or more substituent(s) having no influence on the reaction. Examplesof the substituent include those exemplified with regard to theabove-mentioned optionally substituted alkyl, and the like.

The position and number of the substituents on alkenyl are notparticularly limited.

The cycloalkyl ring formed by R¹ and R² in combination together with theadjacent carbon atom is preferably cycloalkyl ring having 3 to 7 carbonatoms, which is exemplified by cyclopropyl ring, cyclobutyl ring,cyclopentyl ring, cyclohexyl ring, cycloheptyl ring, and the like, withpreference given to that having 4 to 6 carbon atoms such as cyclobutylring, cyclopentyl ring and cyclohexyl ring.

Examples of aryl include phenyl, naphthyl, biphenyl, and the like, withpreference given to phenyl.

The optionally substituted aryl includes, for example, theabove-mentioned aryl which may be substituted by one or moresubstituent(s) having no influence on the reaction. Examples of thesubstituent include those exemplified with respect to theabove-mentioned optionally substituted alkyl; alkyl having 1 to 6 carbonatom(s) such as methyl, ethyl, propyl, butyl, pentyl and hexyl; alkenylhaving 2 to 6 carbon atoms such as vinyl, allyl, butenyl, pentenyl andhexenyl; acyloxy having 2 to 6 carbon atoms such as acetyloxy,propionyloxy, butyryloxy, pivaloyloxy and hexanoyloxy; and the like.Preferred are alkyl, hydroxy, halogen atom, amino, nitro, alkoxy andacyloxy, and more preferred are alkyl, hydroxy, halogen atom, alkoxy andacyloxy.

While the position and number of the substituents on aryl are notparticularly limited, preferred are compounds having 1 to 3 substituentsand more preferred are compounds having 1 or 2 substituents.

The aryl moiety of aralkyl is exemplified by those mentioned above suchas phenyl, naphthyl and biphenyl, and the like. The alkyl moiety thereofis exemplified by those mentioned above having 1 to 6 carbon atom(s),and the like. The aralkyl is exemplified by benzyl, phenethyl,phenylpropyl, phenylbutyl, phenylhexyl and the like. Preferred isaralkyl comprising phenyl with C₁ -C₄ alkyl.

The optionally substituted aralkyl is that which may be substituted byone or more substituent(s) exerting no influence on the reaction.Examples of the substituent include those exemplified with respect tothe aforementioned optionally substituted aryl; haloalkyl having 1 to 6carbon atom(s) such as chloromethyl, chloroethyl and chlorobutyl; andthe like. Preferred are hydroxy, halogen atom, alkyl, alkoxy, haloalkyl,nitro, acyloxy, amino and cyano. More preferred are halogen atom, alkyl,alkoxy and acyloxy. The optionally substituted aralkyl is specificallyexemplified by benzyl, halogen-substituted benzyl, alkyl-substitutedbenzyl, alkoxy-substituted benzyl, phenethyl, halogen-substitutedphenethyl, alkyl-substituted phenethyl, alkoxy-substituted phenethyl,phenylpropyl, halogen-substituted phenylpropyl, alkyl-substitutedphenylpropyl, alkoxy-substituted phenylpropyl, and the like. Preferredare benzyl, phenethyl, and the like.

While the position and number of the substituents on aryl of theabove-mentioned aralkyl are not particularly limited, preferred arecompounds having 1 to 3 substituent(s).

Heteroaryl is, for example, pyridyl, pyrimidyl, pyrazinyl, furyl,thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl,naphthyridinyl, quinazolinyl, cinnolinyl or quinoxalinyl, withpreference given to quinolyl, isoquinolyl, and the like.

The optionally substituted heteroaryl is that which may be substitutedby one or more substituent(s) exerting no influence on the reaction.Examples of the substituent include those exemplified with respect tothe aforementioned optionally substituted aryl. Preferred are alkyl,hydroxy, halogen atom, amino, nitro, mono- or dialkylamino, alkoxy,acyloxy, carboxyl and alkoxycarbonyl. More preferred are alkyl, hydroxy,halogen atom, mono- or dialkylamino, alkoxy and acyloxy.

While the position and number of the substituents on heteroaryl are notparticularly limited, preferred are compounds having 1 to 3substituent(s), and more preferred are compounds having 1 or 2substituent(s).

The heteroaryl moiety of the heteroarylalkyl includes, for example,those exemplified above and the alkyl moiety includes, for example,those exemplified above having 1 to 6 carbon atom(s). Specific examplesinclude 2-thienylmethyl, 3-furylmethyl, 4-pyridylmethyl,2-quinolylmethyl, 3-isoquinolylmethyl and the like. Preferred is2-quinolylmethyl.

The optionally substituted heteroarylalkyl is that which may besubstituted by one or more substituent(s) exerting no influence on thereaction. Examples of the substituent include those exemplified withrespect to the aforementioned optionally substituted heteroaryl, and thelike.

While the position and number of the substituents on heteroaryl of theabove-mentioned heteroarylalkyl are not particularly limited, preferredare compounds having 1 to 3 substituent(s).

The hetero ring to be formed by R⁷ and R⁸ together with the adjacentnitrogen atom is, for example, saturated or unsaturated heteroarylhaving one or more nitrogen atom(s). Specific examples includeimidazolyl, triazolyl, tetrazolyl, pyrrolyl, pyrrolidinyl,imidazolidinyl, hydropyridyl, piperidino, piperazinyl, oxazinyl,morpholino, azepinyl, hydroazepinyl, indolyl, hydroindolyl, isoindolyl,hydroisoindolyl, hydroquinolyl, hydroisoquinolyl, and the like.Preferred are the groups represented by the following formulas ##STR29##wherein the broken line may be either double bond or single bond, andmore preferred is the group represented by the following formula:##STR30##

Said hetero ring may be substituted by halogen atom; alkyl having 1 to 6carbon atom(s); alkenyl having 2 to 6 carbon atoms; alkoxy having 1 to 6carbon atom(s); amino; alkoxycarbonyl having 2 to 6 carbon atoms;carboxamide; or alkyl-substituted carbamoyl wherein the alkyl moiety has1 to 6 carbon atom(s).

While the position and number of substituents on the hetero ring are notparticularly limited, preferred are compounds having 1 to 3substituent(s) and more preferred are compounds having 1 or 2substituent(s).

The halogen atom as the substituent for hetero ring includes, forexample, fluorine, chlorine, bromine and iodine.

The alkyl as the substituent for hetero ring includes, for example, theaforementioned ones having 1 to 6 carbon atom(s).

The alkenyl as the substituent for hetero ring includes, for example,those mentioned above preferably having 2 to 6 carbon atoms.

The alkoxy as the substituent for hetero ring includes, for example,linear or branched alkoxy preferably having 1 to 6 carbon atom(s), whichis exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy, and the like. More preferred are those having 1 to 4 carbonatom(s) such as methoxy, ethoxy, propoxy, isopropoxy and butoxy, withfurther preference given to those having 1 or 2 carbon atom(s) such asmethoxy and ethoxy.

The alkoxycarbonyl as the substituent for hetero ring includes, forexample, alkoxycarbonyl preferably having 2 to 6 carbon atoms, which isexemplified by the above-mentioned alkoxy having 1 to 5 carbon atom(s)with carbonyl group, and the like.

The alkyl-substituted carbamoyl as the substituent for hetero ringincludes, for example, those wherein the alkyl moiety preferably has 1to 6 carbon atom(s), which is exemplified by N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-t-butylcarbamoyl,N-pentylcarbamoyl, N-hexylcarbamoyl, and the like. Preferred isN-t-butylcarbamoyl.

The amino-protecting group includes, for example, optionally substitutedaralkylidene such as benzylidene, 4-chlorobenzylidene,4-nitrobenzylidene, salicylidene, α-naphthylidene and β-naphthylidene;optionally substituted aralkyl such as benzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl,bis(4-methoxyphenyl)methyl and trityl;

optionally substituted acyl such as formyl, acetyl, propionyl, butyryl,pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2-iodoacetyl,2,2-dichloroacetyl, 2,2,2-trichloroacetyl, 2,2,2-trifluoroacetyl,phenylacetyl, phenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl,4-nitrobenzoyl, naphthylcarbonyl and adamantylcarbonyl;

optionally substituted alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, cyclohexyloxycarbonyl,2-chloroethoxycarbonyl, 2-iodoethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-t-butoxycarbonyl,benzhydryloxycarbonyl, bis-(4-methoxyphenyl)methoxycarbonyl,phenacyloxycarbonyl, 2-trimethylsilylethoxycarbonyl,2-triphenylsilylethoxycarbonyl and fluorenyl-9-methoxycarbonyl;

optionally substituted alkenyloxycarbonyl such as vinyloxycarbonyl,2-propenyloxycarbonyl, 2-chloro-2-propenyloxycarbonyl,3-methoxycarbonyl-2-propenyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl,2-butenyloxycarbonyl and cinnamyloxycarbonyl; phenoxycarbonyl;

optionally substituted aralkyloxycarbonyl such as benzyloxycarbonyl,4-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl and phenethyloxycarbonyl;

optionally substituted lower alkylsilyl such as trimethylsilyl andt-butyldimethylsilyl;

optionally substituted alkylthiocarbonyl such as methylthiocarbonyl,ethylthiocarbonyl, butylthiocarbonyl and t-butylthiocarbonyl;

optionally substituted aralkylthiocarbonyl such as benzylthiocarbonyl;

optionally substituted phosphoryl such as dicyclohexylphosphoryl,diphenylphosphoryl, dibenzylphosphoryl, di-(4-nitrobenzyl)phosphoryl andphenoxyphenylphosphoryl; and

optionally substituted phosphinyl such as diethylphosphinyl anddiphenylphosphinyl. It may be phthaloyl as occasion demands. Preferredis aralkyloxycarbonyl and more preferred is benzyloxycarbonyl.

Examples of hydroxy-protecting group include ether protecting groupssuch as methoxymethyl, methoxyethyl, tetrahydropyranyl, benzyl andtrityl; silyl ether protecting groups such as trimethylsilyl andt-butyldimethylsilyl; ester protecting groups such as acetyl, pivaloyl,benzoyl, toluoyl, p-nitrobenzoyl and p-methoxybenzoyl; and the like.Preferred is ester protecting group, with more preference given top-nitrobenzoyl.

The substituent (Z group) which functions as a leaving group togetherwith oxygen atom includes, for example, as a group joining with oxygenatom (leaving group: OZ group), sulfonic acid derivatives such astosyloxy (p-toluenesulfonyloxy), brosyloxy (p-bromobenzene-sulfonyloxy),mesyloxy (methanesulfonyloxy), benzenesulfonyloxy, camphorsulfonyloxyand trifyloxy (trifluoromethanesulfonyloxy), with preference given tomesyloxy (methanesulfonyloxy).

Examples of salts include, but not limited to, alkali metal salts suchas sodium salt, potassium salt and cesium salt; alkaline earth metalsalts such as calcium salt and magnesium salt; organic amine salts suchas triethylamine salt, pyridine salt, picoline salt, ethanolamine salt,triethanolamine salt, dicyclohexylamine salt andN,N'-dibenzylethylenediamine salt; inorganic acid salts such ashydrochloride, hydrobromide, sulfate and phosphate; organic acid saltssuch as formate, acetate, trifluoroacetate, maleate and tartrate;sulfonates such as methanesulfonate, benzenesulfonate andp-toluenesulfonate; amino acid salts such as arginine, aspartate andglutamate; and the like.

The present invention encompasses various isomers of respectivecompounds.

The method for producing compound XV! from (z)-2-butene-1,4-diol whichis used as a starting compound, that is, the method for producingcompounds inclusive of the above-mentioned final objective compound XVI!useful as an HIV protease inhibitor is described in detail in thefollowing. ##STR31## wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and Z are asdefined above and R³ is aralkylamine residue or amino acid derivativeresidue.

Step (1): Protection of diol

The reaction per se is known wherein (z)-2-butene-1,4-diol I! is reactedwith an acetalating agent or a ketalating agent without solvent or in asuitable solvent, in the presence of a dehydrating agent or a suitablecatalyst such as an acid, thereby to protect hydroxyl groups and producecompound II!.

Examples of the acetalating agent and ketalating agent include carbonylcompounds such as formaldehyde, acetaldehyde, benzaldehyde, acetone,diethyl ketone, methyl ethyl ketone, acetophenone, cyclopentanone andcyclohexanone; gem-dialkoxy compounds such as dimethoxymethane,1,1-dimethoxyacetaldehyde, benzaldehydodimethyl-acetal,2,2-dimethoxypropane and cyclohexanone dimethylacetal; vinyl ethercompounds such as methyl vinyl ether, ethyl vinyl ether,2-methoxypropene, 2-ethoxypropene and 1-methoxycyclohexene; and thelike. Preferred are gem-dialkoxy compounds, with more preference givento 2,2-dimethoxypropane.

The catalyst is appropriately selected according to the kind ofacetalating agent and ketalating agent. Suitable catalyst includes, forexample, inorganic acids such as sulfuric acid, hydrochloric acid andnitric acid; and organic acids such as acetic acid, trifluoroaceticacid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acidand camphorsulfonic acid. Preferred are organic acids, with morepreference given to p-toluenesulfonic acid.

Examples of the dehydrating agent include phosphorus pentoxide,molecular sieves, phosphorus pentachloride, and the like. Preferred aremolecular sieves.

The solvent is appropriately selected according to the kind ofacetalating agent and ketalating agent. Suitable solvent includes, forexample, hydrocarbon solvents such as benzene, toluene, hexane andxylene; ether solvents such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran and diglyme; halogen solvents such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solventssuch as ethyl acetate, methyl acetate and butyl acetate; and polarsolvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrileand acetone, with preference given to hydrocarbon solvents and morepreference given to a reaction without solvent.

The reaction (refluxing) temperature is suitably 0-200° C., preferably80-160° C.

The compound II! can be used directly in the next step withoutisolation.

Step (2): Epoxidation with oxidizing agent

This step comprises epoxidation of compound II! without solvent or in asuitable solvent using an oxidizing agent to give compound III!. LikeStep (1), this reaction per se is known (see U.S. Pat. No. 4,439,613).

As the oxidizing agent, inorganic oxidizing agents such as hydrogenperoxide, Oxon (trademark); and organic oxidizing agents such asm-chloroperbenzoic acid, peracetic acid and t-butylhydroperoxide can beused. Preferred are inorganic oxidizing agents and more preferred ishydrogen peroxide. In this case, sodium hydroxide, or sodium hydroxideand disodium hydrogenphosphate in combination are desirably co-used forsmooth progress of the reaction.

The solvent is appropriately selected according to the kind of oxidizingagent. Suitable solvents include, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,acetonitrile, acetone, formic acid, acetic acid and water; and mixedsolvents thereof. Preferred are alcohol solvents and more preferred is amixed solvent of methanol, acetonitrile and water.

While the reaction temperature varies depending on the oxidizingconditions, it is suitably 0-150° C. and preferably 50-100° C. Thereaction time is preferably 3 to 8 hours.

The compound III! can be used directly in the next step withoutisolation.

Step (3): Epoxy ring-opening reaction with chiral amine

This step comprises epoxy ring-opening of compound III! with chiralamine IV! of the formula: R³ --NH₂ wherein R³ is as defined above, in asuitable solvent or without solvent, and subjecting the mixture ofisomers thus produced to crystallization (e.g. recrystallization) togive an optically pure compound V! or an enantiomer thereof.

The chiral amine is an amine having an asymmetric carbon atom adjacentto amino, that is, an amine having an (R) or (S) configuration, which istypically exemplified by aralkylamine, amino acid derivatives, and thelike.

Examples of aralkylamine include (R)-1-phenylethylamine,(S)-1-phenylethylamine, (R)-1-(1-naphthyl)ethylamine,(S)-1-(1-naphthyl)ethylamine, (R)-α-phenylglycinol,(S)-α-phenylglycinol, and the like. Preferred is (R)-1-phenylethylamine.

Examples of amino acid derivative include amino acids such as(R)-serine, (S)-serine, (R)-α-phenylglycine and (S)-α-phenylglycine;amino acid derivatives such as (R)-serine methyl ester, (S)-serinemethyl ester, (R)-α-phenylglycine methyl ester and (S)-α-phenylglycinemethyl ester, and the like. Preferred is (R)-α-phenylglycine.

Aralkylamine residue and amino acid derivative residue at R³respectively mean a group which is other than amino group and whichbinds to amino group in the above-mentioned aralkylamine and amino acidderivative.

By appropriately selecting the chiral amine, a compound V! or anenantiomer of compound V! can be obtained.

Suitable solvents to be used for the reaction include, for example,alcohol solvents such as methanol, ethanol, n-propyl alcohol, isopropylalcohol, n-butyl alcohol and t-butyl alcohol; hydrocarbon solvents suchas benzene, toluene, hexane and xylene; ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred are alcohol solvents and more preferred is isopropylalcohol.

The reaction temperature is suitably 0-150° C. and preferably 50-100° C.The reaction time is preferably 20 to 30 hours.

Suitable solvents to be used for crystallization include, for example,alcohol solvents such as methanol, ethanol, n-propyl alcohol, isopropylalcohol, n-butyl alcohol and t-butyl alcohol; hydrocarbon solvents suchas benzene, toluene, hexane, heptane, methylcyclohexane and xylene;ether solvents such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran and diglyme; halogen solvents such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solventssuch as ethyl acetate, methyl acetate and butyl acetate; polar solventssuch as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetoneand water; and mixed solvents thereof. Preferred are hydrocarbonsolvents and a mixed solvent of hydrocarbon solvent and alcohol solventand more preferred is a mixed solvent of hexane or heptane, andisopropyl alcohol.

Step (4): Removal of chiral element

This step comprises removing chiral element (R³) under suitableconditions from the compound V! or an enantiomer thereof obtained inStep (3) to give a chiral compound VI! or an enantiomer thereof.

The conditions of removal are appropriately determined according to thekind of chiral element. For example, when R³ is 1-phenylethyl, thechiral element can be removed by catalytic reduction in a suitablesolvent in the presence of a suitable catalyst such as palladiumhydroxide, and hydrogen source.

In this case, suitable catalyst includes, for example, palladiumcatalysts (e.g., palladium hydroxide-carbon, palladium-carbon andpalladium-alumina), platinum catalysts (e.g., platinum oxide), rhodiumcatalysts (e.g., rhodium-alumina) and ruthenium catalysts (e.g.,ruthenium-alumina). Preferred are to palladium catalysts with morepreference given to palladium hydroxide-carbon.

Examples of the hydrogen source include hydrogen gas, ammonium formate,formic acid, cyclohexadiene, and the like. Preferred is hydrogen gas.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide, formicacid, acetic acid and water; and mixed solvents thereof. Preferred arealcohol solvents, polar solvents and a mixed solvent of alcohol solventand polar solvent, and more preferred is a mixed solvent of isopropylalcohol, acetic acid and water.

The reaction temperature is suitably 0-100° C. and preferably 20-60° C.The reaction time is preferably 5 to 20 hours.

Step (5): Protection of amino

This step comprises reacting compound VI! or an enantiomer thereofobtained in Step (4), with an acid halide or acid anhydridecorresponding to R⁴ under appropriate conditions, thereby to protect theamino thereof with a protecting group (R⁴) to obtain compound VII! or anenantiomer thereof.

Examples of the amino-protecting group (R⁴) include those mentionedabove.

The acid halide corresponding to R⁴ is not particularly limited as longas it corresponds to R⁴ and exemplified by benzyloxycarbonyl chloride,ethoxycarbonyl chloride, and the like. The acid anhydride correspondingto R⁴ is not particularly limited as long as it corresponds to R⁴ andexemplified by di-t-butyldicarbonate,di-(2,2,2-trichloro-t-butyl)dicarbonate, and the like.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred is a two phase solvent of ester solvent and water andmore preferred is a two phase solvent of ethyl acetate and water.

The reaction temperature is suitably 0-100° C. and preferably 20-60° C.The reaction time is preferably 2 to 10 hours.

Step (6): Isomerization from 7-membered ring to 5-membered ring

This step comprises isomerizing the 7-membered ring moiety of compoundVII! or an enantiomer thereof using a suitable acid in a suitablesolvent into a thermodynamically advantageous 5-membered ring structure,whereby compound VIII! or an enantiomer thereof is obtained.

Suitable acid includes, for example, inorganic acids such as sulfuricacid, hydrochloric acid and nitric acid; and organic acids such asacetic acid, trifluoroacetic acid, methanesulfonic acid,p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium,benzenesulfonic acid and camphorsulfonic acid, with preference given toorganic acid and more preference given to p-toluenesulfonic acidpyridinium.

Suitable solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane and xylene; ether solvents such as diethylether 1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solventssuch as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile and acetone; and mixed solventsthereof. Preferred is polar solvent and more preferred is acetone.

The reaction temperature is suitably 0-100° C. and preferably 20-50° C.The reaction time is preferably 2 to 6 hours.

Step (7): Thioetherification of hydroxy

This step comprises reacting compound VIII! or an enantiomer thereofwith a halogenating agent or a sulfonylating agent in a suitable solventin the presence of a suitable base to convert the hydroxy thereof into asuitable leaving group, and, with or without isolation, reacting theobtained compound with a desired mercaptan of the formula: R⁵ SH whereinR⁵ is as defined above, in the presence of a suitable base to givecompound IX! or an enantiomer thereof.

Suitable leaving group includes, for example, halogen such as chlorine,bromine and iodine; and sulfonyloxy such as methanesulfonyloxy,trifluoromethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy andcamphorsulfonyloxy, with preference given to sulfonyloxy and morepreference given to methanesulfonyloxy.

As the halogenating agent, usable are, for example, phosphorus chloride,phosphorus oxychloride, phosphorus bromide, thionyl chloride andphosphorus pentachloride.

Examples of sulfonylating agent include sulfonyl chloride such asmethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonylchloride and camphorsulfonyl chloride; sulfonic anhydride such asmethanesulfonic anhydride and trifluoromethanesulfonic anhydride, andthe like. Preferred is sulfonyl chloride and more preferred ismethanesulfonyl chloride.

Examples of suitable base include organic base such as pyridine,lutidine, picoline, triethylamine, diisopropylethylamine,dimethylaminopyridine, DBU (1,8-diazabicyclo 5.4.0!-7-undecene), DBN(1,5-diazabicyclo 4.3.0!-5-nonene), and the like. Preferred are pyridineand triethylamine, particularly triethylamine.

Suitable solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane and xylene; ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile and acetone; and mixed solventsthereof. Preferred is polar solvent and more preferred isN,N-dimethylformamide.

The desired mercaptan may be any as long as it has mercapto group, andincludes, for example, optionally substituted arylmercaptans such asthiophenol and toluenethiol; optionally substituted alkylmercaptans suchas methylmercaptan, ethylmercaptan, propylmercaptan, isopropylmercaptan,butylmercaptan, isobutylmercaptan, s-butylmercaptan andt-butylmercaptan; optionally substituted aralkylmercaptans such asbenzylmercaptan, phenethylmercaptan and naphthylmethylmercaptan; andoptionally substituted alkenylmercaptans such as vinylmercaptan andallylmercaptan. Preferred are arylmercaptans and more preferred isthiophenol.

Suitable base to be used for the reaction with desired mercaptansincludes, for example, organic bases such as pyridine, lutidine,picolin, triethylamine, diisopropylethylamine, dimethylaminopyridine,DBU and DBN; and inorganic bases such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate and potassium carbonate, withpreference given to inorganic bases, more preferably potassiumcarbonate.

The reaction temperature is suitably 0-100° C. and preferably 0-50° C.The reaction time is preferably 5-20 hours.

Step (8): Removal of diol-protecting group

This step comprises hydrolyzing acetal or ketal moiety of compound IX!or an enantiomer thereof in a suitable solvent in the presence of asuitable acid to give a diol compound X! or an enantiomer thereof.

Suitable acid includes, for example, inorganic acids such ashydrochloric acid, sulfuric acid and nitric acid; and organic acids suchas acetic acid, trifluoroacetic acid, benzenesulfonic acid,p-toluenesulfonic acid and camphorsulfonic acid, with preference givento inorganic acid and more preference given to hydrochloric acid.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, propyl alcohol, isopropyl alcohol, n-butyl alcohol,isobutyl alcohol, s-butyl alcohol and t-butyl alcohol; ether solventssuch as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme;polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide,acetonitrile, acetone and water; and mixed solvents thereof. Preferredis alcohol solvent, and more preferred is methanol.

The reaction temperature is suitably 0-100° C. and preferably 20-80° C.The reaction time is preferably 30 minutes to 2 hours.

Step (9): Protection of primary hydroxy and conversion of secondaryhydroxy to leaving group

This step comprises reacting compound X! or an enantiomer thereof withan acid halilde or acid anhydride corresponding to R⁶ in a suitablesolvent in the presence of a base to protect the primary hydroxy thereofwith a protecting group R⁶, and, with or without isolation, reacting theobtained compound with a sulfonylating agent to convert the secondaryhydroxy to a leaving group (OZ), whereby compound XI! or an enantiomerthereof is obtained.

Suitable base includes, for example, organic base such as pyridine,lutidine, picoline, triethylamine, diisopropylethylamine,dimethylaminopyridine, DBU and DBN; and inorganic base such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, sodiumhydrogencarbonate, sodium carbonate and potassium carbonate, withpreference given to organic base, particularly triethylamine.

Suitable solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane and xylene; ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile and acetone; and mixed solventsthereof. Preferred is ether solvent and more preferred istetrahydrofuran.

The hydroxy-protecting group (R⁶) includes those exemplified above.

The agent for introducing protecting group is, for example, acid halideor acid anhydride corresponding to R⁶, which is appropriately selectedaccording to the kind of the protecting group. For example, anhydride oracid chloride of the corresponding carboxylic acid is used in the caseof ester protecting group, which is preferably exemplified byp-nitrobenzoyl chloride.

Examples of the leaving group (OZ) include, as mentioned above, sulfonicacid derivatives such as tosyloxy (p-toluenesulfonyloxy), brosyloxy(p-bromobenzenesulfonyloxy), mesyloxy (methanesulfonyloxy),benzenesulfonyloxy, camphorsulfonyloxy, triphiloxy(trifluoromethanesulfonyloxy), and the like. Preferred is mesyloxy(methanesulfonyloxy).

Examples of suitable sulfonylating agent include sulfonyl chloride suchas methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonylchloride and camphorsulfonyl chloride, sulfonic anhydride such asmethanesulfonic anhydride and trifluoromethanesulfonic anhydride, andthe like. Preferred is sulfonyl chloride, and more preferred ismethanesulfonyl chloride.

The reaction temperature is suitably 0-20° C. and preferably 0-10° C.The reaction time is preferably 1 to 5 hours.

Step (10): Epoxidation

This step comprises treating compound XI! or an enantiomer thereof witha suitable base in a suitable solvent to simultaneously carry outdeprotection of primary hydroxy and epoxidation, thereby to introducecompound XII! or an enantiomer thereof.

Suitable base includes, for example, inorganic bases such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide,barium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate and calcium carbonate; and organic bases such asalkoxides (e.g., sodium methoxide, sodium ethoxide and potassiumt-butoxide), with preference given to inorganic base, particularlypotassium hydroxide.

Suitable solvent is appropriately selected according to the base to beused. Examples thereof include alcohol solvents such as methanol,ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol andt-butyl alcohol; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, diglyme and 1,4-dioxane; polarsolvents such as N,N-dimethylformamide, dimethyl sulfoxide,acetonitrile, acetone and water; mixed solvents thereof; and the like.Preferred is a mixed solvent of ether solvent and water, and morepreferred is a mixed solvent of 1,4-dioxane and water.

The reaction temperature is suitably 0-30° C. and preferably 0-20° C.The reaction time is preferably 30 minutes to 5 hours.

Step (11): Epoxy ring opening with amine and removal of amino-protectinggroup

This step comprises treating compound XII! or an enantiomer thereof withamine XIII! in a suitable solvent to open epoxy ring and, with orwithout isolation, removing amino-protecting group (R⁴) to give compoundXIV! or an enantiomer thereof.

The amine may be any as long as it has at least one hydrogen atom onnitrogen, and is exemplified by ammonia, methylamine, ethylamine,propylamine, isopropylamine, aniline, anisidine, dimethylamine,diethylamine, dipropylamine, diisopropylamine, methylethylamine,methylisopropylamine, methylaniline, pyrrolidine, piperidine,decahydroisoquinoline, (3S, 4aS, 8aS)-decahydroisoquinoline-3-carboxylicacid t-butylamide, and the like.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred is alcohol solvent, and more preferred is isopropylalcohol.

The reaction temperature of ring opening with amine is suitably 0-100°C. and preferably 50-80° C. The reaction time is preferably 1 to 10hours.

The method for eliminating amino-protecting group (R⁴) can be suitablyselected according to the kind of the protecting group. When theprotecting group is a carbamate such as t-butoxycarbonyl andbenzyloxycarbonyl, for example, the compound is treated with a suitablebase in a suitable solvent for deprotection.

Suitable base includes, for example, inorganic bases such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide,barium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate and calcium carbonate; and organic bases such asalkoxides (e.g., sodium methoxide, sodium ethoxide and potassiumt-butoxide), ammonia, methylamine, ethylamine, dimethylamine anddiethylamine, with preference given to inorganic base, particularlypotassium hydroxide.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone andwater; and mixed solvents thereof. Preferred is a mixed solvent ofalcohol solvent and water, and more preferred is a mixed solvent ofisopropyl alcohol and water.

The reaction temperature is suitably 0-100° C. and preferably 50-80° C.The reaction time is preferably 5 to 20 hours.

Step (12): Modification of amino

This step comprises acylating the amino group of compound XIV! or anenantiomer thereof with a desirable acylating agent in a suitablesolvent in the presence of a base and, where necessary, removing theprotecting group on R⁹ to give compound XV! or an enantiomer thereof.

Suitable base includes, for example, organic bases such as pyridine,lutidine, picoline, triethylamine, diisopropylethylamine,dimethylaminopyridine, DBU and DBN; and inorganic bases such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, sodiumhydrogencarbonate, sodium carbonate and potassium carbonate, withpreference given to inorganic base, particularly sodiumhydrogencarbonate.

The acylating agent may be any as long as it reacts with primary amino,and is exemplified by optionally substituted alkylcarboxylic anhydridessuch as acetic anhydride and pivalic anhydride; optionally substitutedarylcarboxylic anhydrides such as benzoic anhydride and toluicanhydride; optionally substituted alkylcarbonyl chlorides such as acetylchloride and pivaloyl chloride; optionally substituted arylcarbonylchlorides such as benzoyl chloride and toluoyl chloride; optionallysubstituted heteroarylcarboxylic anhydrides and optionally substitutedheteroarylcarbonyl chlorides; optionally substituted aralkylcarboxylicanhydrides and optionally substituted aralkylcarbonyl chlorides;optionally substituted heteroarylalkylcarboxylic anhydrides andoptionally substituted heteroarylalkylcarbonyl chlorides; and the like.In addition, an acid chloride having a protecting group, such as3-acetoxy-2-methylbenzoyl chloride can be used.

Suitable solvent is appropriately selected according to the kind of thebase to be used. Examples thereof include alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; mixed solventsthereof; and the like. Preferred is a two phase solvent of ester solventand water and more preferred is a two phase solvent of ethyl acetate andwater.

The reaction temperature is suitably 0-20° C. and preferably 0-10° C.The reaction time is preferably 30 minutes to 3 hours.

When the above-mentioned acylating agent has a protecting group, suchprotecting group may be eliminated.

The method for deprotection is appropriately selected according to thekind of the protecting group. For example, when3-acetoxy-2-methylbenzoyl chloride is used as an acylating agent, theacetyl group as the protecting group can be removed by treating thecompound with a suitable base in a suitable solvent.

Examples of protecting group include acetyl, pivaloyl, benzoyl,trichloroacetyl, trifluoroacetyl, and the like.

Suitable base includes, for example, organic bases such as amines (e.g.,ammonia, methylamine, ethylamine, dimethylamine and diethylamine); andinorganic bases such as lithium hydroxide, sodium hydroxide, potassiumhydroxide, sodium hydrogencarbonate, sodium carbonate and potassiumcarbonate, with preference given to amines, particularly ammonia.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred is alcohol solvent and more preferred is methanol.

The reaction temperature is suitably 0-100° C. and preferably 20-50° C.The reaction time is preferably 1 to 5 hours.

The enantiomers of the above-mentioned compound XV! and variousintermediates can be obtained by the same reactions as above using anenantiomer of compound V! obtained in Step (3).

The compound XV!, various intermediates and enantiomers thereof can beobtained at optional purity by appropriately applying known methods forseparation and purification, such as concentration, extraction,chromatography, reprecipitation and recrystallization.

The salts of the above-mentioned compound XV!, various intermediates andvarious isomers thereof can be produced by a known method.

The present invention is described in detail by way of illustrativeExamples in the following, to which the invention is not limited.

Examples are shown in a schematic flow in the following. ##STR32##wherein Ph is phenyl, Ac is acetyl, Cbz is benzyloxycarbonyl, Ms ismethanesulfonyl and Bu-t is t-butyl.

REFERENCE EXAMPLE 1 Production of Compound 2! (Step 1)

To a mixture of (z)-2-butene-1,4-diol (compound 1!, 211.4 g, 2.4 mol)and 2,2-dimethoxypropane (590.2 ml, 4.8 mol) was added p-toluenesulfonicacid monohydrate (30 mg). The solution thus obtained was evaporatedunder atmospheric pressure to give a colorless transparent liquid of2,2-dimethyl-4,7-dihydro-1,3-dioxepine (compound 2!, 245 g, yield 80%),melting point 140-145° C./760 mmHg.

¹ H-NMR (CDCl₃, 300 MHz) δ: 5.67 (diffused s, 2H), 4.26 (diffused s,4H), 1.44 (s, 6H)

REFERENCE EXAMPLE 2 Production of Compound 3! (Step 2)

2,2-Dimethyl-4,7-dihydro-1,3-dioxepine (compound 2!, 94.0 g, 0.734 mol),methanol (220 ml) and acetonitrile (116 ml, 2.20 mol) were mixed and themixture was heated to 60° C. A 30% aqueous hydrogen peroxide solution(208 ml, 1.84 mol) was dropwise added over 1.5 hours at 60-70° C.Simultaneously, an aqueous solution of 1M sodium hydroxide was dropwiseadded to adjust the reaction system to a pH of 9.1-9.6. Even after thedropwise addition of the aqueous solution of hydrogen peroxide, thedropwise addition of the aqueous solution of 1M sodium hydroxide wascontinued, during which time the pH was kept at 9.1-9.6 and temperatureat 50-70° C., and the mixture was stirred for 1.5 hours. The reactionmixture was cooled to room temperature, diluted with saturated brine(220 ml) and extracted with chloroform (180 ml×1, 90 ml×2). The organiclayers were combined, washed with an aqueous solution of sodium hydrogensulfite (300 ml, 15 g) and dried over magnesium sulfate. The solvent wasevaporated and the residue was distilled to give a colorless,transparent liquid of 4,4-dimethyl-3,5,8-trioxabicyclo 5.1.0!octane(compound 3!, 86.7 g, yield 82%), melting point 70-74° C./17 mmHg.

¹ H-NMR (CDCl₃, 300 MHz) δ: 4.08-3.97 (m, 4H), 3.22-3.18 (m, 2H), 1.37(s, 3H), 1.32 (s, 3H)

REFERENCE EXAMPLE 3 Production of Compound 5! (Step 3)

4,4-Dimethyl-3,5,8-trioxabicyclo 5.1.0!octane (compound 3!, 142 g, 0.988mol) obtained above and (R)-1-phenylethylamine (compound 4!, 120 g,0.988 mol) were dissolved in isopropyl alcohol (400 ml). The mixture wasrefluxed under heating for 24 hours and concentrated to 366 g. Hexane(400 ml) was added to the residue and the mixture was stirred at 5° C.for one hour. The precipitated crystals were collected by filtration,washed with hexane and dried to give colorless crystals of (5R,6S)-2,2-dimethyl-6- (R)-1-phenylethylamino!-1,3-dioxepan-5-ol (compound5!, 94.0 g, yield 36%), melting point 108-108.5° C.

¹ H-NMR (CDCl₃, 300 MHz) δ: 7.33-7.22 (m,5H), 3.95 (q,1H,J=6.5 Hz), 3.75(dd,1H,J=1.8,12.1 Hz), 3.74 (dd,1H,J=2.0,12.5 Hz), 3.52 (dd,1H,J=5.5,12.5 Hz), 3.48 (ddd,1H,J=0.5,5.9,12.1 Hz), 3.37 (dt,lH,J=1.4,5.6Hz), 2.44 (br s,1H), 2.34 (dt,1H,J=1.7,5.5 Hz), 1.34 (d,3H,J=6.5 Hz),1.34 (s,3H), 1.31 (s,3H)

IR (KBr): 3406, 2590, 1452, 1374, 1219, 1072, 1052, 841, 758, 696 cm⁻¹

α!_(D) ²⁵ : +91.0° (c1.00, MeOH)

Elemental Analysis (C₁₅ H₂₃ NO₃) Calculated: C,67.90;H,8.74;N,5.28.Found: C,67.90;H,9.01;N,5.31.

REFERENCE EXAMPLE 4 Production of Compound 6! (Step 4)

20% Palladium hydroxide-carbon (50% wet type, 9.20 g) was suspended inisopropyl alcohol (550 ml), and (5R, 6S)-2,2-dimethyl-6-(R)-1-phenylethylamino!-1,3-dioxepan-5-ol (compound 5!, 92.0 g, 37.7mmol) and acetic acid (20.8 ml, 37.7 mmol) were added. The mixture wasstirred at room temperature under hydrogen atmosphere (3.0 atm) for 8hours. The catalyst was removed by Celite filtration and the filtratewas concentrated to 105 g. Hexane (400 ml) was added to the residue andthe obtained suspension was stirred to allow precipitation of thincrystals. The crystals were collected by filtration and dried to givecolorless crystals of (5R, 6S)-6-amino-2,2-dimethyl-1,3-dioxepan-5-olacetate (compound 6!, 76.6 g, yield 100%), melting point 133-134° C.

¹ H-NMR (CDCl₃, 300 MHz) δ: 3.84 (dd,1H,J=2.5,12.7 Hz), 3.74(dd,1H,J=2.5,12.5 Hz), 3.67-3.53 (m,3H), 2.98 (dt,J=2.4,6.5 Hz), 1.91(s,3H), 1.33 (s,6H)

IR (KBr): 3178, 2993, 1617, 1561, 1525, 1409, 1385, 1223, 1087, 1031,846 cm⁻¹

α!_(D) ²⁵ : +29.6° (c1.05, MeOH)

Elemental Analysis (C₉ H₁₉ NO₅): Calculated: C,48.86;H,8.66;N,6.33.Found: C,48.98;H,8.70;N,6.36.

EXAMPLE 1 Production of Compound 7! (Step 5)

(5R, 6S)-6-Amino-2,2-dimethyl-1,3-dioxepan-5-ol acetate (compound 6!,29.0 g, 0.131 mol) and sodium hydrogencarbonate (33.0 g, 0.393 mol) wereadded with stirring to a suspension of water (150 ml) and ethyl acetate(50 ml). A solution of benzyl chloroformate (18.7 ml, 0.131 mol) inethyl acetate (50 ml) was dropwise added to the mixture with stirring,and the mixture was stirred at room temperature for 6 hours. The organiclayer was separated and washed successively with a 0.5 M aqueous citricacid solution (30 ml), a saturated aqueous solution of sodiumhydrogencarbonate (30 ml) and saturated brine (30 ml), and dried overmagnesium sulfate. The solution was distilled away under reducedpressure to give (5R,6S)-6-benzyloxycarbonylamino-2,2-dimethyl-5-hydroxy-1,3-dioxepane(compound 7!, 38.5 g, yield 99.5%) as a colorless oil.

¹ H-NMR (CDCl₃, 300 MHz) δ: 7.4-7.3 (m,5H), 5.39 (brd.d,1H), 5.13(d,J=12.1 Hz,1H), 5.07 (d,J=12.1 Hz,1H), 3.99 (d,J=12.7 Hz,1H), 3.79(d,J=12.9 Hz,1H), 3.8-3.6 (m,2H), 3.57 (m,1H), 3.49 (ddd, J=12.8,2.8,1.8Hz,1H), 2.73 (brd.s,1H), 1.34 (s,3H), 1.32 (s,3H)

IR (neat): 3334, 2942, 1703, 1508, 1454, 1376, 1288, 1218, 1157, 1049,854 cm⁻¹

α!_(D) ²⁵ : +38.8° (c1.45, MeOH)

MS (FAB): m/z 296 M+H!⁺, Calculated: 296.1501, Found: 296.1498 rationalformula: C₁₅ H₂₂ NO₅

EXAMPLE 2 Production of Compound 8! (Step 6)

A crude product of (5R,6S)-6-benzyloxycarbonylamino-2,2-dimethyl-5-hydroxy-1,3-dioxepane(compound 7!, 38.5 g) was dissolved in acetone (200 ml) andp-toluenesulfonic acid pyridinium (1.31 g, 5.2 mmol) was added. Themixture was heated at 50-55° C. for 4 hours. After cooling to roomtemperature, toluene (400 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (100 ml) were added. The organic layer was separatedand washed successively with a saturated aqueous solution of sodiumhydrogencarbonate (100 ml) and water (100 ml). After drying overmagnesium sulfate, the residue was concentrated under reduced pressureto give (2S)-2-benzyloxycarbonylamino-2-(4R)-2,2-dimethyl-1,3-dioxolan-4-yl!ethanol (compound 8!, 36.0 g, yield94%).

¹ H-NMR (CDCl₃, 300 MHz) δ: 7.5-7.2 (m,5H), 5.32 (brd.d,1H), 5.15(d,J=12.2 Hz,1H), 5.09 (d,J=12.2 Hz,1H), 4.4-4.3 (m,1H), 4.05 (t, J=7.5Hz,1H), 3.9-3.6 (m,4H), 2.54 (bs,1H), 1.42 (s,3H), 1.35 (s,3H)

IR (neat): 3440, 2985, 2938, 2885, 1703, 1530, 1454, 1372, 1250, 1216,1156, 1069, 856 cm⁻¹

α!_(D) ²⁵ : -23.5° (c1.02, MeOH)

MS (FAB): m/z 296 M+H!⁺, Found: 296.1491, Calculated: 296.1498 rationalformula: C₁₅ H₂₂ NO₅

EXAMPLE 3 Production of Compound 9! (Step 7)

A crude product of (2S)-2-benzyloxycarbonylamino-2-(4R)-2,2-dimethyl-1,3-dioxolan-4-yl!ethanol (compound 8!, 36.0 g) andtriethylamine (17.0 ml, 0.122 mol) were dissolved inN,N-dimethylformamide (360 ml), and the mixture was cooled to 4° C.Methanesulfonyl chloride (9.40 ml, 0.122 mol) was dropwise added at4-12° C., and after the dropwise addition, the mixture was stirred at 4°C. for 30 minutes. Then, potassium carbonate (33.7 g, 0.244 mol) andthiophenol (12.5 ml, 0.122 mol) were successively added under a nitrogenatmosphere, and the mixture was stirred at room temperature for 16hours. After the completion of the reaction, toluene (500 ml) was addedto the mixture. The mixture was washed successively with water (200 ml),a 10% aqueous potassium carbonate solution (150 ml), saturated brine(150 ml), a 0.5 M aqueous citric acid solution (150 ml), a saturatedaqueous solution of sodium hydrogencarbonate (150 ml) and saturatedbrine (150 ml). After drying over magnesium sulfate, the solvent wasdistilled away under reduced pressure to give(1R)-1-benzyloxycarbonylamino-1-(4R)-2,2-dimethyl-1,3-dioxolan-4-yl!-2-phenylthioethane (compound 9!,45.0 g, yield 98%) as an oil.

¹ H-NMR (CDCl₃, 300 MHz) δ: 7.5-7.0 (m,10H), 5.2-5.0 (m,3H), 4.50(td,J=6.9,1.8 Hz,1H), 3.99 (m,1H), 3.86 (m,1H), 3.66 (dd, J=8.1,7.0Hz,1H), 3.24 (dd,J=13.8,5.9 Hz,1H), 3.04 (dd,J=13.8,8.6 Hz,1H), 1.42(s,3H), 1.30 (s,3H)

MS (FAB): m/z 388 M+H!⁺, Found: 388.1588, Calculated: 388.1583 rationalformula: C₂₁ H₂₆ NO₄ S

EXAMPLE 4 Production of Compound 10! (Step 8)

A crude product of (1R)-1-benzyloxycarbonylamino-1-(4R)-2,2-dimethyl-1,3-dioxolan-4-yl!-2-phenylthioethane (45.0 g) wasdissolved in methanol (360 ml) and 0.1N hydrochloric acid (90 ml) wasadded, which was followed by heating for one hour at 80° C. After thereaction mixture was concentrated under reduced pressure, a saturatedaqueous solution of sodium hydrogencarbonate (100 ml) and water (50 ml)were added and the mixture was extracted with ethyl acetate (400 ml×2).The obtained organic layers were combined, washed with saturated brine(100 ml) and dried over magnesium sulfate. The solvent was distilledaway under reduced pressure to give(2R,3R)-3-benzyloxycarbonylamino-4-phenylthio-1,2-butanediol (compound10!; 39.0 g, yield 94%) as an oil.

¹ H-NMR (CDCl₃, 300 MHz) δ: 7.5-7.0 (m,10H), 5.27 (brd.d,1H), 5.09(s,2H), 4.01 (m,1H), 3.86 (m,1H), 3.6-3.4 (m,2H), 3.21 (dd, J=13.7,6.7Hz,1H), 3.12 (dd,J=13.7,7.5 Hz,1H), 2.62 (brd.d,1H), 2.52 (m,1H)

EXAMPLE 5 Production of Compound 11! (Step 9)

(2R,3R)-3-Benzyloxycarbonylamino-4-phenylthio-1,2-butanediol (compound10!, 39.0 g) and triethylamine (39.1 ml, 0.280 mol) were dissolved intetrahydrofuran (300 ml) and the mixture was cooled to not more than 5°C. p-Nitrobenzoyl chloride (20.8 g, 0.112 mol) was added to the mixtureat 3-10° C., and the mixture was stirred for one hour under ice-cooling.Then, methanesulfonyl chloride (10.4 ml, 0.135 mol) was dropwise addedat 2-12° C. and the mixture was stirred under ice-cooling for one hour.After the completion of the reaction, insoluble matter was filtered offand washed with ethyl acetate. The filtrate and the washing werecombined and concentrated under reduced pressure. The obtained residuewas again dissolved in ethyl acetate (300 ml). This solution was washedsuccessively with water (50 ml), a 0.5 M aqueous citric acid solution(50 ml), a saturated aqueous solution of sodium hydrogencarbonate (50ml) and saturated brine (50 ml). After drying over magnesium sulfate,the solvent was distilled away under reduced pressure. The obtainedresidue was recrystallized from toluene (400 ml)/diisopropyl ether (300ml) to give(2R,3R)-3-benzyloxycarbonylamino-4-phenylthio-2-methanesulfonyloxy-1-(4-nitrobenzoyloxy)butane(compound 11!, 38.6 g, yield 51%, from(5R,6S)-6-amino-2,2-dimethyl-5-hydroxy-1,3-dioxepane) as colorlesscrystals.

¹ H-NMR (CDCl₃, 300 MHz) δ: 8.5-8.0 (m,4H), 7.5-7.2 (m,10H), 5.44(ddd,J=6.9,5.1,2.3 Hz,1H), 5.11 (s,2H), 5.09 (brd.d,1H), 4.57(dd,J=12.0,6.9 Hz,1H), 4.50 (dd,J=12.0,5.1 Hz,1H), 4.21 (m,1H), 3.25(dd,J=14.0,6.2 Hz,1H), 3.05 (s,3H), 3.05 (dd,J=14.0,8.2 Hz,1H)

IR (KBr): 3347, 1725, 1699, 1531, 1514, 1349, 1283, 1172, 1109, 1028,925 cm⁻¹

α!_(D) ²⁵ : -14.0° (c1.01, CHCl₃)

Elemental Analysis (C₂₆ H₂₆ N₂ O₉ S₂): Calculated:C,54.35;H,4.56;N,4.88. Found: C,54.49;H,4.19;N,4.75.

EXAMPLE 6 Production of Compound 12! (Step 10)

(2R,3R)-3-Benzyloxycarbonylamino-4-phenylthio-2-methanesulfonyloxy-1-(4-nitrobenzoyloxy)butane(compound 11!, 15.0 g, 26.1 mol) was dissolved in 1,4-dioxane (120 ml)and a 2N aqueous potassium hydroxide solution (28.7 ml, 57.4 mmol) wasadded. The mixture was stirred for one hour at room temperature andtoluene (200 ml) was added. The mixture was washed successively withwater (200 ml), a saturated aqueous solution of sodium hydrogencarbonate(200 ml) and saturated brine (100 ml). After drying over magnesiumsulfate, the solvent was distilled away under reduced pressure to give(2S,3R)-3-benzyloxycarbonylamino-4-phenylthio-1-buteneoxide (compound12!, 8.43 g, yield 98%) as a colorless oil.

¹ H-NMR (CDCl₃, 300 MHz) δ: 7.5-7.1 (m,10H), 5.2-5.0 (m,3H), 3.70(m,1H), 3.22 (d,J=5.6 Hz,2H), 2.99 (m,1H), 2.9-2.6 (m,2H)

IR (KBr): 3302, 1694, 1538, 1323, 1256, 1100, 1028, 1006, 882 cm⁻¹

α!_(D) ²⁵ : -26.2° (c1.01, CHCl₃)

Elemental Analysis (C₁₈ H₁₉ NO₃ S): Calculated: C,65.63;H,5.81;N,4.25.Found: C,65.36;H,5.85;N,4.33.

EXAMPLE 7 Production of Compound 14! (Step 11)

A crude product of(2S,3R)-3-benzyloxycarbonylamino-4-phenylthio-1-buteneoxide (compound12!, 8.43 g) and (3S,4aS,8aS)-decahydroisoquinoline-3-carboxylic acidt-butylamide (compound 13!, 4.98 g, 20.9 mmol) were dissolved inisopropyl alcohol (70 ml), and the mixture was heated at 70-75° C. for 5hours. Then, a 2N aqueous potassium hydroxide solution (52.3 ml, 104.5mmol) was added and the mixture was further heated at 70-75° C. for 15hours. After cooling to room temperature, toluene (120 ml) was added andthe mixture was washed with water (120 ml). The organic layer wasextracted with 1N hydrochloric acid (80 ml×1, 40 ml×1) and the aqueoussolutions obtained were combined and washed with toluene (100 ml×3).This aqueous solution was adjusted to pH 12 with a 5N aqueous potassiumhydroxide solution and extracted with toluene (120 ml). The organiclayer was washed with saturated brine. After drying over magnesiumsulfate, the solvent was distilled away under reduced pressure to give(3S,4aS,8aS)-2-((2R,3R)-3-amino-2-hydroxy-4-phenylthiobutyl)-decahydroisoquinoline-3-carboxylicacid t-butylamide (compound 14!, 9.39 g, yield 85%) as a colorless oil.

¹ H-NMR (CDCl₃, 300 MHz) δ: 7.5-7.1 (m,5H), 6.05 (brd.s,1H), 3.68(m,1H), 3.37 (dd,J=13.0,2.8 Hz,1H), 3.02-2.88 (m,2H), 2.83 (dd,J=13.0,9.8 Hz,1H), 2.64 (dd,J=13.2,5.1 Hz,1H), 2.60 (dd,J=8.0,3.7Hz,1H), 2.30 (dd,J=13.2,6.6 Hz,1H), 2.27 (dd,J=11.8,3.3 Hz,1H), 1.32(s,9H), 2.0-1.0 (m,12H)

EXAMPLE 8 Production of Compound 15! (Step 12)

(3S,4aS,8aS)-2-((2R,3R)-3-Amino-2-hydroxy-4-phenylthiobutyl)-decahydroisoquinoline-3-carboxylicacid t-butylamide (compound 14!, 9.39 g) and sodium hydrogencarbonate(4.55 g, 54.2 mmol) were added to a suspension of water (40 ml) andethyl acetate (40 ml). A solution of 3-acetoxy-2-methylbenzoyl chloride(4.37 g, 20.6 mmol) in ethyl acetate (40 ml) was dropwise added to thesuspension with stirring under ice-cooling. The mixture was furtherstirred for one hour under ice-cooling and water (20 ml) was added. Theorganic layer was separated and washed with a saturated aqueous solution(20 ml) of sodium hydrogencarbonate. After drying over magnesiumsulfate, the solvent was distilled away under reduced pressure to give(3S,4aS,8aS)-2-(2R,3R)-3-(3-acetoxy-2-methylbenzoylamino)-2-hydroxy-4-phenylthiobutyl!decahydroisoquinoline-3-carboxylicacid t-butylamide (12.7 g, yield 96%) as colorless amorphous.

¹ H-NMR (CDCl₃, 300 MHz) δ: 7.5-7.1 (m,8H), 7.1-7.0 (m,1H), 5.51(brd.s,1H), 4.48 (m,1H), 4.07 (m,1H), 3.81 (dd,J=13.7,9.2 Hz,1H), 3.41(dd,J=13.7,4.7 Hz,1H), 2.91 (dd,J=11.7,2.0 Hz,1H), 2.56 (dd, J=12.9,9.1Hz,1H), 2.44 (m,1H), 2.32 (s,3H), 2.27 (s,3H), 2.3-2.1 (m,2H), 1.99(m,1H), 1.9-1.1 (m,11H), 1.07 (s,9H)

The obtained (3S,4aS,8aS)-2- (2R,3R)-3-(3-acetoxy-2-methylbenzoylamino)-2-hydroxy-4-phenylthiobutyl!decahydroisoquinoline-3-carboxylicacid t-butylamide (12.7 g) was dissolved in methanol (96 ml) and 28%aqueous ammonia (24 ml) was added, which was followed by stirring for1.5 hours. The resulting precipitate was collected by filtration andwashed with a mixed solution of methanol (75 ml)/water (25 ml). Theresidue was dried at 50° C. under reduced pressure to give(3S,4aS,8aS)-2-(2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl!decahydroisoquinoline-3-carboxylicacid t-butylamide (compound 15!, 8.00 g, yield 54%, from(2R,3R-benzyloxycarbonylamino-4-phenylthio-2-methanesulfonyloxy-1-(4-nitrobenzoyloxy)butane)as colorless crystals.

¹ H-NMR (CD₃ OD, 300 MHz) δ: 7.49 (m,2H), 7.27 (m,2H), 7.17 (m,1H), 7.01(m,1H), 6.90 (m,1H), 6.79 (m,1H), 4.43 (m,1H), 4.06 (m,1H), 3.54(dd,J=10.1,3.5 Hz,1H), 3.37 (m,1H), 3.04 (dd,J=8.7,1.7 Hz,1H), 2.60(m,2H), 2.24 (s,3H), 2.17 (m,2H), 2.01 (m,1H), 1.9-1.1 (m,11H), 1.17(s,9H)

EXAMPLE 9 Production of Methanesulfonate of Compound 15!

(3S,4aS,8aS)-2-(2R,3R)-2-Hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl!decahydroisoquinoline-3-carboxylicacid t-butylamide (compound 15!, 7.80 g, 13.7 mmol) was suspended intetrahydrofuran (40 ml) and methanesulfonic acid (0.918 ml, 14.1 mmol)was added, which was stirred until the solid was completely dissolved.The mixture was dropwise added to methyl-t-butyl ether (470 ml) (afterrinsing with 5 ml of tetrahydrofuran). Precipitate was producedinstantaneously with the dropwise addition. The mixture was stirred atroom temperature for 2 hours after the dropwise addition. Theprecipitate was collected by filtration, washed with methyl-t-butylether (27 ml) and dried at 65° C. for one day under reduced pressure togive (3S,4aS,8aS)-2-(2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl!decahydroisoquinoline-3-carboxylicacid t-butylamide methanesulfonate (8.68 g, yield 95%) as a colorlesssolid.

¹ H-NMR (CD₃ OD, 300 MHz) δ: 7.93 (brd.s,1H), 7.43 (m,1H), 7.30 (m,2H),7.22 (m,1H), 7.03 (t,J=5.9 Hz,1H), 6.86 (m,2H), 4.19 (m,1H), 4.08(m,1H), 3.61 (dd,J=9.7,1.3 Hz,1H), 3.45 (dd,J=10.4,2.6 Hz,1H), 3.38(dd,J=9.8,2.9 Hz,1H), 3.28 (m,1H), 3.17 (m,1H), 3.05 (dd, J=10.4,7.7Hz,1H), 2.68 (s,3H), 2.26 (s,3H), 2.2-2.1 (m,12H), 1.30(s,9H)

The production method of the present invention is extremely easy andsimple as compared to the conventional methods, and enables effectiveproduction of compound XV! at high yields, which includes compound XVI!having an HIV protease inhibitory action. In addition, the novelintermediates of the present invention are extremely useful asintermediates for producing not only the aforementioned compound XVI!but also compounds useful as X-ray contrast media such as the compoundsfor X-ray image development as described in U.S. Pat. No. 4,439,613.

What is claimed is:
 1. A 1,3-dioxolan-4-yl-ethanol derivative of theformula VIII! ##STR33## wherein R¹ and R² are the same or different andeach is a hydrogen atom, an alkyl or an aryl, or R¹ and R² combinedlyform a cycloalkyl ring together with the adjacent carbon atom, and R⁴ isan amino-protecting group selected from the group consisting of anoptionally substituted aralkylidene, an optionally substituted aralkylexcept benzyl, an optionally substituted acyl, an optionally substitutedalkoxycarbonyl, an optionally substituted alkenyloxycarbonyl,phenoxycarbonyl, an optionally substituted aralkyloxycarbonyl, anoptionally substituted lower alkylsilyl, an optionally substitutedalkylthiocarbonyl, an optionally substituted aralkylthiocarbonyl, anoptionally substituted phosphoryl and an optionally substitutedphosphinyl, an enantiomer thereof or a salt thereof.
 2. A1,3-dioxolan-4-yl-ethylthio derivative of the formula IX! ##STR34##wherein R¹ and R² are the same or different and each is a hydrogen atom,an alkyl or an aryl, or R¹ and R² combinedly form a cycloalkyl ringtogether with the adjacent carbon atom, R⁴ is an amino-protecting groupand R⁵ is a hydrogen atom, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted aryl or anoptionally substituted aralkyl, an enantiomer thereof or a salt thereof.3. A method for producing a 1,3-dioxolan-4-yl-ethanol derivative of theformula VIII! ##STR35## wherein R¹ and R² are the same or different andeach is a hydrogen atom, an alkyl or an aryl, or R¹ and R² combinedlyform a cycloalkyl ring together with the adjacent carbon atom, and R⁴ isan amino-protecting group selected from the group consisting of anoptionally substituted aralkylidene, an optionally substituted aralkylexcept benzyl, an optionally substituted acyl, an optionally substitutedalkoxycarbonyl, an optionally substituted alkenyloxycarbonyl,phenoxycarbonyl, an optionally substituted aralkyloxycarbonyl, anoptionally substituted lower alkylsilyl, an optionally substitutedalkylthiocarbonyl, an optionally substituted aralkylthiocarbonyl, anoptionally substituted phosphoryl and an optionally substitutedphosphinyl, or an enantiomer thereof, comprising isomerizing a(5R,6S)-6-substituted amino-1,3-dioxepan-5-ol derivative of the formulaVIII! ##STR36## wherein R¹, R² and R⁴ are as defined above, or anenantiomer thereof into a 5-membered ring in the presence of an acid. 4.A method for producing a 1,3-dioxolan-4-yl-ethanol derivative of theformula VIII! ##STR37## wherein R¹ and R² are the same or different andeach is a hydrogen atom, an alkyl or an aryl, or R¹ and R² combinedlyform a cycloalkyl ring together with the adjacent carbon atom, and R⁴ isan amino-protecting group selected from the group consisting of anoptionally substituted aralkylidene, an optionally substituted aralkylexcept benzyl, an optionally substituted acyl, an optionally substitutedalkoxycarbonyl, an optionally substituted alkenyloxycarbonyl,phenoxycarbonyl, an optionally substituted aralkyloxycarbonyl, anoptionally substituted lower alkylsilyl, an optionally substitutedalkylthiocarbonyl, an optionally substituted aralkylthiocarbonyl, anoptionally substituted phosphoryl and an optionally substitutedphosphinyl, or an enantiomer thereof, comprising protecting an aminogroup of a (5R,6S)-6-amino-1,3-dioxepan-5-ol derivative of the formulaVI! ##STR38## wherein R¹ and R² are as defined above, or an enantiomerthereof, to give a (5R,6S)-6-substituted amino-1,3-dioxepan-5-olderivative of the formula VII! ##STR39## wherein R¹, R² and R⁴ are asdefined above, an enantiomer thereof or a salt thereof, and isomerizingthe obtained compound into a 5-membered ring in the presence of an acid.5. A method for producing a 1,3-dioxolan-4-yl-ethylthio derivative ofthe formula IX! ##STR40## wherein R¹ and R² are the same or differentand each is a hydrogen atom, an alkyl or an aryl, or R¹ and R²combinedly form a cycloalkyl ring together with the adjacent carbonatom, R⁴ is an amino-protecting group selected from the group consistingof an optionally substituted aralkylidene, an optionally substitutedaralkyl except benzyl, an optionally substituted acyl, an optionallysubstituted alkoxycarbonyl, an optionally substitutedalkenyloxycarbonyl, phenoxycarbonyl, an optionally substitutedaralkyloxycarbonyl, an optionally substituted lower alkylsilyl, anoptionally substituted alkylthiocarbonyl, an optionally substitutedaralkylthiocarbonyl, an optionally substituted phosphoryl and anoptionally substituted phosphinyl, and R⁵ is a hydrogen atom, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted aryl or an optionally substituted aralkyl, or anenantiomer thereof, comprising reacting a 1,3-dioxolan-4-yl-ethanolderivative of the formula VIII! ##STR41## wherein R¹, R² and R⁴ are asdefined above, or an enantiomer thereof, with a halogenating agent or asulfonylating agent, and reacting the obtained compound with a mercaptanof the formula

    R.sup.5 SH

wherein R⁵ is as defined above, for thioetherification.